Process for preparing isoquinoline compounds

ABSTRACT

The invention relates to novel compounds of the general formula (I), ##STR1## The compounds of the invention antagonize the effects of constrictive mediators, e.g. histamine, acetylcholine or serotonin; they show an antiallergic action and possess an antiinflammatory effect. Thus, these compounds can therapeutically be used as bronchodilators as well as antiallergic or antiinflammatory drugs, particularly in the treatment of bronchial asthma.

This is a divisional of co-pending application Ser. No. 07/792,255 filedon Nov. 14, 1991, now U.S. Pat. No. 5,179,089.

FIELD OF THE INVENTION

This invention relates to novel compounds of the formula (I), ##STR2##wherein R means hydrogen or a straight or branched chain C₁₋₆ alkoxygroup;

R¹ stands for hydrogen or a straight or branched chain C₁₋₆ alkyl group;

R² represents hydrogen or a straight or branched chain C₁₋₆ alkyl group;

R³ means hydrogen; a straight or branched chain C₁₋₆ alkyl groupoptionally substituted by one or two hydroxyl and/or one or two straightor branched chain C₁₋₄ alkoxy groups; or a C₄₋₇ cycloalkyl group;

R⁴ stands for hydrogen or a straight or branched chain C₁₋₆ alkyl groupoptionally substituted by one or two hydroxyl and/or one or two straightor branched chain C₁₋₄ alkoxy groups; or a C₄₋₇ cycloalkyl group; or

R³ and R⁴ together with the nitrogen atom, to which they are attachedform a 4 to 8-membered cyclic group of formula ##STR3## optionallysubstituted by one or two straight or branched chain C₁₋₄ alkoxy and/orone or two straight or branched chain C₁₋₄ alkyl groups, whereoptionally an oxygen or sulfur atom or an N-R⁵ group may be substitutedfor a ring carbon atom, where R⁵ means hydrogen or a straight orbranched chain C₁₋₆ aliphatic alkyl group, the 4- to 8-membered cycleoptionally being condensed with a benzene ring;

R⁶ stands for hydrogen or a C₁₋₁₀ acyl group

and their salts. The invention also relates to the pharmaceuticalcompositions containing these compounds.

The invention relates also to a process for the preparation of the abovenew compounds and compositions.

The compounds of formula (I) are unknown in the literature.

R as alkoxy means inter alia a methoxy, ethoxy, propyloxy, isopropyloxy,butoxy, pentoxy or hexyloxy group.

R¹ and R² may stand e.g. for methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiary butyl, secondary butyl, pentyl or isopentyl group.

R³ and R⁴ may mean inter alia the groups defined for R¹ or R² as well as2-hydroxyethyl or cyclohexyl group. ##STR4## may stand inter alia for apiperidinyl, piperazinyl, 4-methyl-1-piperazinyl, morpholinyl,hexamethylenimino or 1-pyrrolidinyl group.

BACKGROUND OF THE INVENTION

R⁶ may represent e.g. an acetyl or benzoyl group.

The frequency of occurrence of allergic diseases, particularly bronchialasthma is continuously increasing. Social-economical and environmentalconditions, enhancement of effectivity of the diagnostics and the lackof an adequate, really healing therapy provide background for thisincrease. Despite of or partially even due to the elevated drugconsumption, the mortality ratio also shows a rising tendency.

Asthma is characterized by an increased sensitivity of the respiratorysmooth muscles to the most various stimuli, which leads to a reversibleconstriction or obstruction of the airways. Chronic asthma eventuallyresults in an irreversible airway obstruction.

Here, an uncontrolled inflammatory process of the respiratory tractappears to be involved. A therapy, which is based only on abronchodilatation without affecting and even masking the above processrepresents a merely symptomatic treatment which is essentially harmfuland likely contributes to the increase in the mortality.

In opposition to this, an antiinflammatory therapy suppresses theinflammation and at least slows down the harmful background process aswell as diminishes the frequency of the demand on a simultaneously usedbronchodilatory treatment.

In the cases of drugs being available at present, a further problemappears in the adverse effects decreasing to a high degree theirusefulness.

Thus, a most advantageous therapy could be ensured by a drug which iseffective against mediator substances causing a spasm of the respiratorysmooth muscles and simultaneously possessing antiinflammatory orantiallergic effect without any adverse side effect.

Due to the pathologic nature of bronchial asthma, the effects againstthe possibly highest number of mediator substances, being constrictiveor even inflammatory in character, is very important since the actionsof many kinds of endogeneous substances are simultaneously exerted. Itwould be arbitrary to suppose an outstanding role of any component.Thus, the simultaneous presence of each of the effects defined above isimportant for these drugs to be developed for the treatment of bronchialasthma.

DESCRIPTION OF THE INVENTION

Now, it has been found during the pharmacological study on the compoundsof formula (I) that these substances antagonize the effects ofconstrictor-type mediators (e.g. histamine, acetylcholine, serotonin),show an antiallergic action and possess an antiinflammatory effect.Thus, the compounds of formula (I) have a bronchodilator-type effect(similarly to the β₂ antagonists or theophylline) as well as anantiallergic or anti-inflammatory action (similarly to theglucocorticoids, cromolyn or nedocromyl).

Therefore, the compounds of general formula (I) extensively satisfy thetherapeutic demands discussed above since they associate thebronchodilatory, antiallergic and antiinflammatory activities with anadvantageous lack of toxic and without harmful side effects (withoutadverse effects).

The invention relates also to a process for the preparation of the newcompounds of formula (I), wherein

R means hydrogen or a straight or branched chain C₁₋₆ alkoxy group;

R¹ stands for hydrogen or a straight or branched chain C₁₋₆ alkyl group;

R² represents hydrogen or a straight or branched chain C₁₋₆ alkyl group;

R³ means hydrogen; a straight or branched chain C₁₋₆ alkyl groupoptionally substituted by one or two hydroxyl and/or one or two straightor branched chain C₁₋₆ alkoxy groups; or a C₄₋₇ cycloalkyl group;

R⁴ stands for hydrogen or a straight or branched chain C₁₋₆ alkyl groupoptionally substituted by one or two hydroxyl and/or one or two straightor branched chain C₁₋₄ alkoxy groups; or a C₄₋₇ cycloalkyl group, or

R³ and R⁴ together with the nitrogen atom, to which they are attachedform a 4 to 8-membered cyclic group of formula ##STR5## optionallysubstituted by one or two straight or branched chain C₁₋₄ alkoxy and/orone or two straight or branched chain C₁₋₄ alkyl groups, whereoptionally an oxygen or sulfur atom or an N--R⁵ group may be substitutedfor a ring carbon atom, where R⁵ means hydrogen or a straight orbranched chain C₁₋₆ aliphatic alkyl group, the 4- to 8-membered cycleoptionally being condensed with a benzene ring;

R⁶ stands for hydrogen or a C₁₋₁₀ acyl group

and their salts, which comprises hydrolyzing a compound of the formula(II), ##STR6## wherein R, R¹ and R² are as defined above and X means ahalide ion, then reacting the obtained derivative of formula (III)##STR7## wherein R, R¹ and R² are as defined above and Me means a metalatom

a) with a racemic or optically active amino alcohol derivative offormula (IV), ##STR8## wherein the ##STR9## group is as defined aboveand Y stands for halogen or arylsulfonyl group, or

b) with an epoxypropylamine derivative of the formula (V) ##STR10##wherein the ##STR11## group is as defined above, then, if desired,acylating the thus obtained active compounds of formula (I), wherein R,R¹, R², R³, R⁴ and R⁵ are as defined above and R⁶ stands for hydrogen,by known methods to obtain compounds of the formula (I), wherein R⁶ isas defined above, except hydrogen; or resolving the racemic compounds offormula (I) by known methods; or converting the racemic or opticallyactive compounds of formula (I) to their salts; or liberating the freecompounds of formula (I) from their salts.

According to the process of the invention the compounds of formula (II)can be hydrolyzed in aqueous organic solvents, preferably in aqueousaliphatic alcohols by adding a base, suitably an alkaline metalhydroxide. According to a preferred embodiment of this reaction thealkaline metal hydroxide or the aqueous solution thereof is added to thereaction mixture, then the reaction is carried out at the boiling pointof the solvent mixture. However, the hydrolysis may be accomplished alsounder stirring at room temperature since the compounds of formula (II)are hydrolyzed also at lower temperatures.

Although the hydrolysis of compounds of the formula (II) starts evenafter adding 1 molar equivalent of alkali, this process is rather low,therefore it is suitable to use the alkali in excess. When the compoundsof formula (III) are reacted with compounds of the formula (IV) or theirsalts or with the salts of compounds of the formula (V), the amount ofalkali needed to liberate the base from the latter salts may already beadded to the reaction mixture during the hydrolysis of the compounds offormula (II). On reacting the thiols of formula (III) with the salts ofthe compounds of formula (IV) it is suitable to carry out the reactionin the presence of 2 to 6 moles of alkali. The amount of the base usedis proportionally diminished when the compounds of formula (IV) or (V)are added in their base form to the reaction mixture.

It is suitable to react the thiols of formula (III), present in solutionas their salts after hydrolysis, without isolation with the compounds offormula (IV) or (V). The compounds of formula (IV) or (V) may be addedas their solid salts to the reaction mixture. However alternatively,after dissolving the salts of the compounds of formula (IV) or (V) inwater or in a mixture of water with a water-miscible organic solvent,preferably an alcohol, their solutions may be added dropwise to thereaction mixture. The addition may be carried out while refluxing thereaction mixture but a lower temperature may also be used. Thesubstances of formula (IV) or (V) can also be employed in their freebase form; the addition may be achieved by using or without a solvent.

After adding the compounds of formula (IV) or (V) the reaction mixtureis further boiled under a reflux condenser or stirred at a lowertemperature, if desired, even under cooling. The compounds of formula(I) formed in the reaction remain in solution in their free base form.After termination of the reaction the products of formula (I) areisolated by using commonly known working up methods. The organic solventis preferably evaporated under reduced pressure, whereby the product offormula (I) is separated in an oily or crystalline form from theremaining aqueous medium. Any crystalline base of the formula (I) isseparated from the mother liquor by filtration whereas the oily crudeproducts are extracted from the aqueous phase. The extraction may becarried out by using water-immiscible solvents, e.g. ethers,hydrocarbons, halogenated hydrocarbons and the like commonly employedfor this purpose. After extraction the solutions are dried and thesolvent is evaporated under reduced pressure. The evaporation residue isan oily product which becomes crystalline in several cases whilestanding or by rubbing as both crystalline and oily substances may occuramong the bases of formula (I).

The crude products of formula (I) can be purified as crude bases oralternatively, the crude bases may be converted to their salts withmineral or organic acids, and, if desired, the salts obtained may besubjected to a further purification. Methods commonly used in thesynthetic organic chemistry such as recrystallization, cromatographicalmethods and the like can be employed for the purification. Preferred andpharmacologically acceptable salts can be formed by using e.g.hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid or phosphoric acid as inorganic acids; or citric acid,acetic acid, formic acid, succinic acid, lactic acid, malonic acid,maleic acid, propionic acid, fumaric acid and ascorbic acid as organicacids. Other organic or inorganic acids are also suitable.

A possibility of separation of optically active antipodes comprisesforming salts of the compounds of formula (I) with optically activeacids and then crystallizing the salts obtained. This method may beaccomplished under the usual conditions of resolution by using commonlyemployed optically active acids such as d-tartaric acid and derivativesthereof, d-camphorsulfonic acid, d-camphoric acid and the like. The saltformation may be carried out in organic solvents or in a mixturethereof. The precipitating crystalline salts are purified byrecrystallization from organic solvents, preferably from alcohols (e.g.ethanol, isopropanol). After resolution the optically active bases areliberated by adding an alkali. The salts of the antipodes formed withmineral acids can be obtained by adding mineral acids without liberatingthe bases; alternatively, these salts may be formed by reacting theoptically active bases with mineral acids.

Compounds of the formula (I) containing a C₁₋₁₀ acyl group as R⁶ areprepared by the acylation of compounds of the formula (I), wherein R⁶ ishydrogen. The acylation may be performed by using acyl halides oranhydrides, preferably in the presence of organic or inorganic bases ina manner known per se. This reaction may be carried out in a solvent orby using an excess of the acylating agent (e.g. acetic anhydride) assolvent. All solvents being inert to the acylating agents (e.g.hydrocarbons, halohydrocarbons, pyridine) are useful for this purpose.The products are isolated by the usual methods, e.g. evaporation andrecrystallization.

The starting substances of formula (II) and the process for theirpreparation are known from the German patent specification No.2,426,267.

The compounds of formula (IV) are known and can be prepared according toJ. Org. Chem. 25, 1424 (1960). The compounds of formula (V) are alsoknown and are prepared as described in J. Am. Chem. Soc. 80, 1257(1958).

SPECIFIC EXAMPLES

The pharmacological effects of the compounds according to the inventionwere investigated by using the methods described hereinafter.

I. Study on the effects against spasmogenic mediators [modified methodof J. C. Castillo et al.: Exp. Ther. 90, 104 (1947)]

The investigation on isolated organs were carried out as follows.

OHF Lt/R9 guinea pigs of both sexes weighing 300 to 400 g each wereanaesthetized by pentobarbital. Their trachea was removed and sectionedin the opposite side to the site of smooth muscle in longitudinaldirection. Subsequently, a strip-like preparation was obtained byserrately cutting.

The organ was suspended in an organ bath containing 35 ml of Krebssolution at 37° C. bubbled through by carbogen gas (consisting of 95% ofoxygen and 5% of carbon dioxide).

A rest load of 0.5 g was used. Several washings were carried out duringthe incubation period of 30 minutes.

The change in the tension of the tracheal smooth muscle was followed byusing an isometric Grass FT-03 type tensiometer sensor device. A washingwas made following the cumulative dose series of the given mediator(e.g. histamine). After reaching the base line, by 15 minutes afteradministration of the given concentration of the inhibitory(antiasthmatic) substance to be tested, the next cumulative dose seriesof the mediator was administered. In the case of an inhibitory action,the strength of effect, following the second dose series of themediator, was increased in comparison to that of the first (control)series.

For characterization of strength of the competitive antagonistic effectthe pA₂ value was determined according to the method of Schield [Br. J.Pharmacol. 4, 277 (1949)]. A pd'₂ value was calculated [J. M. VanRossum: Arch. Int. Pharmacodyn 143, 317 (1963)] to characterize thenoncompatitive antagonistic effectivity. The higher the pA₂ or pd'₂value, respectively were, the higher was the antagonistic effect.

Theophylline was used as reference drug having the following values:

pd'₂ value against histamine: 5.80

pd'₂ value against acetylcholine: 6.43

pd'₂ value against serotonin: 6.49.

The results obtained in the above test by the compounds of formula (I)of the invention are summarized in Table I.

                  TABLE I                                                         ______________________________________                                                     Inhibition of the histamine-induced                              Compound of  constriction of isolated tracheal                                the Example No.                                                                            smooth muscle of guinea pig pd'.sub.2                            ______________________________________                                        1            5.04                                                             2            4.91                                                             3            4.57                                                             4            4.30                                                             5            4.34                                                             6            6.69                                                             7            4.76                                                             8            4.87                                                             9            4.38                                                             10           3.98                                                             11           4.45                                                             12           4.81                                                             13           4.90                                                             14           4.58                                                             15           4.46                                                             16           4.49                                                             17           5.74                                                             18           6.91                                                             19           4.01                                                             20                                                                            21           5.54                                                             22           5.14                                                             23           4.76                                                             24           5.93                                                             25           6.38                                                             26           5.06                                                             27           6.27                                                             28           6.36                                                             theophylline 5.80                                                             ______________________________________                                    

II. Study of the antiallergic effect

1) The effect influencing the active local anaphylactic reaction wasmeasured according to the method of M. Koltay [Arch. Allergy App. Immun.71, 181 (1983)].

Female OFA rats weighing 160 to 180 g each were sensitized by bovineserum albumin (BSA) adsorbed to 50 μg of Al(OH)₃ gel together with thesimultaneous administration of Bordatella pertussis vaccine.

The anaphylactic reaction was elicited by injecting 100 μg of BSA intothe right hind paw plant in the 14th day.

The measurements were carried out before and 30 minutes after elicitingthe reaction. The animals were orally treated with the compound to betested 1 hour before the injection of BSA. The results were expressed aspercentage inhibition compared to the control group (average % ±S.E.M.).

2) The acute antiinflammatory effect was determined by using thecarrageenin-induced rat paw edema test [C. A. Winker et al.: Proc. Soc.Exp. Med. 111, 544 (1962)].

Female CFY rats weighing 100 to 120 g each were used after starvationfor 24 hours.

The inflammation was induced by injecting 0.1 ml of 1% carrageeninsolution into the right hind paw plant.

The severity of inflammation was determined by using an Ugo-Basile typeplethysmometer. The measurement was carried out before and 1.5, 3 and4.5 hours after induction of the inflammation.

The animals were orally treated with the substance to be tested 1 hourbefore administration of carrageenin. The effect was expressed aspercentage inhibition related to the control group.

3) Dextran-induced rat paw edema test

The method of S. Gourvaisier and R. Ducrot [Arch. Int. Pharmacodyn.Ther. 102, 33 (1955)] was employed.

The method described for the carrageenin edema test was followed, exceptthat the measurements were carried out 30, 60, 90, 120 and 180 minutesafter induction of the inflammation.

For the use as medicaments, the compounds of formula (I) and their saltsare formulated to pharmaceutical compositions such as tablet, dragee,suppository, capsule, solution, powder mixture, injectable or inhalationcompositions after adding various additives by methods commonly used inthe pharmaceutical industry. Being in general readily soluble in aqueousmedia, the salts of compounds of the formula (I) are convenient toutilize for the preparation of solutions which can therapeutically beused in both injectable and inhalable compositions.

The reference substances listed hereinafter together with theirpharmacological values were utilized in the investigations discussedhereinabove.

1. Inhibition of the spasmogenic mediator-induced constriction of theisolated tracheal smooth muscle of the guinea pig

    ______________________________________                                                   Histamine                                                                             Serotonin Acetylcholine                                    ______________________________________                                        pd'.sub.2 of theophylline                                                                  5.80      6.16      6.43                                         ______________________________________                                    

2. Effect influencing the active local anaphylactic reaction on rat

    ______________________________________                                                     Oral dose Protective effect %                                    Compound     mg/kg     in the 30th minute                                     ______________________________________                                        Naproxen     30        2.2                                                    BW 755C      50        52.9                                                   Dexamethasone                                                                              0.5       45.5                                                   ______________________________________                                    

3. Carrageenin-induced rat paw edema

    ______________________________________                                                       Protective effect %                                                     Oral dose                                                                             1.5        3      4.5                                        Compound   mg/kg     hours                                                    ______________________________________                                        Naproxen   20        33.2       44.3 40.4                                     ______________________________________                                    

4. Dextran-induced rat paw edema test

    ______________________________________                                                       Protective effect %                                                     Oral dose                                                                             30     60     90    120  180                                 Compound   mg/kg     minutes                                                  ______________________________________                                        Naproxen   20        16.9   20.1 18.9  23.3 21.6                              BW-755C    50        15.4   12.3 17.2   7.9 11.3                              dexamethasone                                                                            0.5       42.7   36.8 51.1  52.1 45.5                              ______________________________________                                    

The invention is further illustrated in detail by the followingnon-limiting Examples.

EXAMPLE 1 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-diethylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride

After dissolving 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-methyl]isothiuroniumbromide (prepared as described in our earlier German patentspecification No. 2,426,267) in the mixture of 80 ml of ethanol and 20ml of water by heating, 16.0 ml of 10% sodium hydroxide solution areadded and the reaction mixture is refluxed for 90 minutes, then 1.7 g of1-chloro-3-diethylamino-2-propanol dissolved in 10 ml of methanol(prepared by reacting diethylamine with epichlorohydrin in methanolaccording to J. Org. Chem. 25, 1424 (1960)) are added dropwise to themixture. After refluxing the reaction mixture for 6 hours and thenevaporating the organic solvent under reduced pressure, concentratedhydrochloric acid is added dropwise to the remaining aqueous-oilyresidue until reaching a pH value of 5 to 6. The solution is clarifiedby activated charcoal, filtered and the filtrate is alkalized by adding10% sodium hydroxide solution. A yellow oil precipitates which becomessolid by rubbing. After filtration and drying, the product is dissolvedin 20 ml of isopropanol and acidified by adding hydrogen chloride inabs. ethanol solution to obtain 1.8 g of the named compound, m.p.: 179°C.

Analysis for C₂₀ H₃₀ ClN₃ O₃ S (molecular weight 427.99) calculated: N9.82; Cl 8.28; S 7.49%; found: N 9.91; Cl 8.40; S 7.50%.

EXAMPLE 2 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-diethylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed, except that 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-methyl]isothiuroniumbromide and 1-chloro-3-diethylamino-2-propanol are used as reactants togive the named compound in a yield of 2.1 g, m.p.: 149° C.

Analysis for C₂₂ H₃₄ ClN₃ O₃ S (molecular weight 456.04): calculated: N9.22; Cl 7.77; S 7.03%; found: N 9.08; Cl 7.93; S 7.31%.

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                               1.5       3        4.5 hours                                  Percentage of the                                                                           -22.9     -20.6    -11.3                                        protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg (p.o.)                                                                           30     60      90   120   180 minutes                             Percentage of                                                                            -24    -21     -25  -23   -17                                      inhibition                                                                    ______________________________________                                    

EXAMPLE 3 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinylidene)-2-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-mercapto-acetonitrilehydrochloride

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]-isothiuroniumbromide and 1-chloro-3-(N-methyl-N-2-hydroxyethyl)-amino-2-propanol asstarting substances to obtain the named compound in a yield of 2.6 mg,m.p.: 136° C. (from abs. ethanol).

    ______________________________________                                        Analysis for C.sub.19 H.sub.28 ClN.sub.3 O.sub.4 S (molecular weight          429.96)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             53.07    6.56   9.77    8.25 7.46%;                                 found:    52.82    6.82   9.40    8.13 7.50%.                                 ______________________________________                                    

EXAMPLE 4 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[3-(N,N-bis-2-hydroxyethyl)-amino-2-hydroxypropyl]-mercapto-acetonitrilehydrochloride dihydrate

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]-isothiuroniumbromide and 1-chloro-3-(N,N-bis-2-hydroxyethyl)-amino-2-propanol asstarting substances to obtain the named compound in a yield of 2.3 g,m.p.: 135° C. (from 96% etanol).

    ______________________________________                                        Analysis for C.sub.20 H.sub.34 ClN.sub.3 O.sub.7 S (molecular weight          496.02)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             48.43    6.91   8.47    7.15 6.46%;                                 found:    48.66    6.77   8.25    7.45 6.31%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                               1.5       3        4.5 hours                                  Percentage of the                                                                           -25.0     -26.0    -24.0                                        protective effect                                                             ______________________________________                                    

EXAMPLE 5 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[3-(N,N-bis-2-hydroxyethyl)-amino-2-hydroxypropyl]mercapto-acetonitrilehydrochloride

The process described in Example 1 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]-isothiuroniumbromide and 1-chloro-3-(N,N-bis-2-hydroxyethyl)-amino-2-propanol asstarting substances to obtain the named compound in a yield of 3.1 g,m.p.: 165° C. (from abs. ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.34 ClN.sub.3 O.sub.5 S (molecular weight          488.04)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             54.14    7.02   8.61    7.27 6.57%;                                 found:    54.14    7.00   8.61    7.31 6.30%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                               1.5       3        4.5 hours                                  Percentage of the                                                                           -21.0     -16.5    -10.0                                        protective effect                                                             ______________________________________                                    

EXAMPLE 6 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-isopropylaminopropyl)mercaptoacetonitrilehydrochloride hemihydrate

The process described in Example 1 is followed, by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]-isothiuroniumbromide and 1-chloro-3-isopropylamino-2-propanol as starting substancesto give the named compound in a yield of 2.6 g, m.p.: 176° C. (fromisopropanol).

    ______________________________________                                        Analysis for C.sub.19 H.sub.28 ClN.sub.3 O.sub.3 S.0.5H.sub.2 O               (molecular weight 422.97)                                                             C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             53.95    6.91   9.94    8.38 7.58%;                                 found:    53.60    6.69   10.24   8.47 7.60%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.) 1.5       3       4.5 hours                                   Percentage of the                                                                             0       -17.0     0                                           protective effect                                                             ______________________________________                                    

EXAMPLE 7 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-isopropylaminopropyl)mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed, by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-isoquinolinylidene)methyl]-isothiuroniumbromide and 1-chloro-3-isopropylamino-2-propanol as starting substancesto obtain the named compound in a yield of 2.8 g, m.p.: 185° C. (fromisopropanol).

    ______________________________________                                        Analysis for C.sub.21 H.sub.32 ClN.sub.3 O.sub.3 S (molecular weight          442.01)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             57.06    7.30   9.51    8.02 7.25%;                                 found:    56.78    7.35   9.70    8.31 7.05%.                                 ______________________________________                                    

EXAMPLE 8 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-tert-butylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride

After adding 80 ml of ethanol and 20 ml of water to 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide, the mixture is heated until dissolution of the solid material(1 to 2 minutes). After adding 16.0 ml of 10% sodium hydroxide solution,the mixture is refluxed for 90 minutes. Subsequently, 2.02 g of3-tert-butylamino-1-chloro-2-propanol hydrochloride (prepared byreacting tert-butylamine with epichlorohydrin in methanol as describedin the literature cited above, then precipitating the salt fromisopropanol solution of the crude base, by adding ethanolic hydrogenchloride solution; m.p. of the hydrochloride: 160° C.) are portionwiseadded to the reaction mixture which is then refluxed for 5 hours,thereafter ethanol is evaporated under reduced pressure. The residue isthe yellow oily crude base, which becomes crystalline while standing,m.p.: 112° C. The crude base is obtained in a yield of 3.6 g.

By adding ethanolic hydrogen chloride solution to an isopropanolsolution of the crude base the named hydrochloride is obtained, m.p.:177° C.

    ______________________________________                                        Analysis for C.sub.20 H.sub.30 ClN.sub.3 O.sub.3 S (molecular weight          427.99)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             56.12    7.07   9.82    8.28 7.49%;                                 found:    56.40    6.87   9.82    8.38 7.72%.                                 ______________________________________                                    

EXAMPLE 9 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-tert-butylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride hemihydrate

The process described in Example 8 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 3-tert-butylamino-1-chloro-2-propanol hydrochloride asstarting substances to obtain the named compound in a yield of 2.4 g,m.p.: 160° C. (from isopropanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.34 ClN.sub.3 O.sub.3 S.0,5H.sub.2 O               (molecular weight 465.05)                                                             C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             56.82    7.59   9.04    7.62 6.90%;                                 found:    56.70    7.76   9.00    7.95 6.82%.                                 ______________________________________                                    

EXAMPLE 10 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-methyl]isothiuroniumbromide and 1-chloro-3-cyclohexylamino-2-propanol as starting substancesto obtain the named product in a yield of 2.7 g, m.p.: 190° C. (fromisopropanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.32 ClN.sub.3 O.sub.3 S (molecular weight          454.02)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             58.20    7.10   9.26    7.81 7.06%;                                 found:    58.00    7.40   9.02    7.81 6.86%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                               1.5       3       4.5 hours                                   Percentage of the                                                                           -14.8     -13.0    -7.2                                         protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg (p.o.)                                                                           30     60      90   120   180 minutes                             Percentage of                                                                            -25    -24     -25  -27   -50                                      inhibition                                                                    ______________________________________                                    

EXAMPLE 11 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxypropyl)mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-cyclohexylamino-2-propanol as starting substancesto obtain the named product in a yield of 2.6 g, m.p.: 182° C. (fromisopropanol).

    ______________________________________                                        Analysis for C.sub.24 H.sub.36 ClN.sub.3 O.sub.3 S (molecular weight          482.08)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             59.79    7.53   8.72    7.36 6.65%;                                 found:    60.02    7.50   8.65    7.16 6.45%.                                 ______________________________________                                    

EXAMPLE 12 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-pyrrolidinyl)propyl]mercaptoacetonitrilehydrochloride hemihydrate

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(1-pyrrolidinyl)-2-propanol as startingsubstances to give 2.1 g of the named product, m.p.: 194° C. (fromethanol).

    ______________________________________                                        Analysis for C.sub.20 H.sub.28 ClN.sub.3 O.sub.3 S.0,5H.sub.2 O               (molecular weight 434.98)                                                             C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             55.22    6.72   9.66    8.15 7.37%;                                 found:    55.18    7.03   9.90    8.15 7.55%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                               1.5       3        4.5 hours                                  Percentage of the                                                                           -27.2     -18.9    -17.6                                        protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg   30      60      90    120   180 minutes                            (p.o.)                                                                        Percentage                                                                              -20.2   -15.6   -14.7 -14.6 -12.6                                   of inhibition                                                                 ______________________________________                                    

EXAMPLE 13 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-pyrrolidinyl)propyl]mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(1-pyrrolidinyl)-2-propanol to obtain the namedproduct in a yield of 2.6 g, m.p.: 195° C. (from ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.32 ClN.sub.3 O.sub.3 S (molecular weight          454.02)                                                                                C    H        N      Cl     S                                        ______________________________________                                        calculated:                                                                              58.20  7.10     9.26 7.81   7.06%;                                 found:     57.92  7.30     9.20 7.48   6.82%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3          4.5   hours                                   Percentage of the                                                                         -31.8    -21.8      -9.05                                         protective effect                                                             ______________________________________                                    

EXAMPLE 14 Preparation of2-(1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-piperidinyl)propyl]mercaptoacetonitrile

The process described in Example 8 is followed by using 3.25 g ofS-[α-cyano-α-(1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(1-piperidinyl)-2-propanol to give the namedproduct in a yield of 2.1 g, m.p.: 103° C. (from isopropanol).

    ______________________________________                                        Analysis for C.sub.19 H.sub.25 N.sub.3 OS (molecular weight 343.48)                     C    H          N      S                                            ______________________________________                                        calculated: 66.43  7.34       12.23                                                                              9.34%;                                     found:      66.17  7.14       12.50                                                                              9.24%.                                     ______________________________________                                    

The hydrochloride of the named product is obtained by adding abs.ethanolic hydrogen chloride solution to the base dissolved in abs.ethanol, m.p.: 187° C.

Inhibition of the active local anaphylactic reaction:

The percentage of inhibition achieved by an oral dose of 50 mg/kg ofbody weight is -44.1% in the 30th minute after induction of thereaction. Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3          4.5   hours                                   Percentage of the                                                                         -20.9    -20.0      -20.0                                         protective effect                                                             ______________________________________                                    

EXAMPLE 15 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-piperidinyl)propil]mercaptoacetonitrilehydrochloride

After dissolving 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide in a mixture of 80 ml of ethanol with 20 ml of water underheating, 16 ml of 10% sodium hydroxide solution are added and thereaction mixture is refluxed for 2 hours, then cooled to roomtemperature and 2.2 g of 1-chloro-3-(1-piperidinyl)-2-propanolhydrochloride are added to the reaction mixture while stirring. Themixture is stirred at room temperature for 2 days and then worked up asdescribed in Example 1. In this way 2.7 g of the named hydrochloride areobtained, m.p.: 210° C. (from ethanol).

    ______________________________________                                        Analysis for C.sub.21 H.sub.30 N.sub.3 O.sub.3 S (molecular weight            440.00)                                                                                 C    H          N      S                                            ______________________________________                                        calculated: 57.32  6.87       9.55 7.29%;                                     found:      56.99  7.01       9.32 7.43%.                                     ______________________________________                                    

EXAMPLE 16 Preparation of2-(1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride hemihydrate

The process described in Example 15 is followed by using 3.25 g ofS-[α-cyano-α-(1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(4-morpholinyl)-2-propanol hydrochloride asstarting substances to obtain 2.7 g of the named product, m.p.: 195° C.(from ethanol).

    ______________________________________                                        Analysis for C.sub.18 H.sub.24 ClN.sub.3 O.sub.2 S.0.5H.sub.2 O               (molecular weight 390.93)                                                               C    H          N      S                                            ______________________________________                                        calculated: 55.30  6.44       10.75                                                                              8.20%;                                     found:      55.10  6.30       10.50                                                                              8.37%.                                     ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3          4.5   hours                                   Percentage of the                                                                         -29.3    -22.2      -20.0                                         protective effect                                                             ______________________________________                                    

EXAMPLE 17 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride

The process described in Example 15 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(4-morpholinyl)-2-propanol hydrochloride asstarting materials to obtain the named compound in a yield of 3.3 g,m.p.: 210° C. (from ethanol).

    ______________________________________                                        Analysis for C.sub.20 H.sub.28 ClN.sub.3 O.sub.4 S (molecular weight          441.97)                                                                                C    H        N      Cl     S                                        ______________________________________                                        calculated:                                                                              54.35  6.39     9.51 8.02   7.26;                                  found:     54.42  6.52     9.63 8.00   7.54;                                  ______________________________________                                    

Inhibition of the active local anaphylactic reaction:

The percentage of inhibition achieved by an oral dose of 50 mg/kg is-53.4% in the 30th minute following induction of the reaction.

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                            1.5         3     4.5   hours                                    Percentage of the                                                                          -4.2        0     0                                              protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg (p.o.)                                                                          30     60      90   120   180  minutes                             Percentage of                                                                            27.5   32.5    32.1 32.4  20.3                                     inhibition                                                                    ______________________________________                                    

EXAMPLE 18 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile

After adding 80 ml of methanol and 20 ml of water to 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide, the reaction mixture is heated until complete dissolution (1 to2 minutes). After adding 11.0 ml of 10% sodium hydroxide solution themixture is refluxed for 90 minutes. After addition of 2.2 g of1-chloro-3-(4-morpholinyl)-2-propanol hydrochloride, the reactionmixture is refluxed for 5 hours. Then, methanol is evaporated and theresidue is cooled down, whereby the crude base crystallizes out to givethe named product in a yield of 3.2 g, m.p.: 97° C. (from abs. ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.31 N.sub.3 O.sub.4 S (molecular weight            433.56)                                                                                 C    H          N      S                                            ______________________________________                                        calculated: 60.94  7.21       9.69 7.40%;                                     found:      60.72  7.40       9.51 7.17%.                                     ______________________________________                                    

The hydrochloride of the above base is precipitated by adding anethanolic solution of hydrogen chloride to an abs. ethanolic solution ofthe base, m.p.: 203° C. (from ethanol).

LD₅₀ i.v.

91.37 mg/kg on male rat

132.98 mg/kg on female rat

165.76 mg/kg on male mouse

150.00 mg/kg on female mouse.

LD₅₀ p.o.

1204.59 mg/kg on male mouse

1034.65 mg/kg on female mouse.

Inhibition of the active topic anaphylactic reaction

The percentage of inhibition achieved by an oral dose of 50 mg/kg is-31% in the 30th minute following the induction of reaction.

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3          4.5   hours                                   Percentage of the                                                                         -35.8    -29.3      -28.4                                         protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg (p.o.)                                                                          30     60      90   120   180  minutes                             Percentage of                                                                            29.8   38.7    30.4 26.3  28.4                                     inhibition                                                                    ______________________________________                                    

EXAMPLE 19 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-hexamethylenimino-2-hydroxypropyl)mercaptoacetonitrile

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-hexamethylenimino-2-propanol as startingmaterials to obtain 1.7 g of the named base as a yellow oil.

The hydrochloride of the above base is precipitated from ethanolicsolution. The hydrochloride crystallizes with 1 mole of crystal ethanoland half mole of crystal water, m.p.: 110° to 112° C. (from ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.31 N.sub.3 O.sub.3 S.HCl.C.sub.2 H.sub.5          OH.0.5H.sub.2 O                                                               (molecular weight 509.10)                                                              C    H        N      Cl     S                                        ______________________________________                                        calculated:                                                                              56.62  7.72     8.25 6.96   6.30%;                                 found:     56.66  8.05     8.20 6.70   6.65%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3          4.5   hours                                   Percentage of the                                                                         -29.0    -24.2      -19.5                                         protective effect                                                             ______________________________________                                    

Inhibition of development of the dextran-induced rat paw edema:

    ______________________________________                                        50 mg/kg                                                                              30      60      90    120   180   minutes                             (p.o.)                                                                        Percentage                                                                            -28.2   -26.6   -27.3 -27.8 -22.8                                     of                                                                            inhibition                                                                    ______________________________________                                    

EXAMPLE 202-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl]mercaptoacetonitrilehydrochloride hydrate

The process described in Example 15 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)-2-propanolas starting materials to yield 3.1 g of named product, m.p.: 140° C.(from ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.30 ClN.sub.3 O.sub.3 S.H.sub.2 O (molecular       weight 506.05)                                                                          C    H          N      Cl                                           ______________________________________                                        calculated: 59.33  6.37       8.30 7.01%;                                     found:      59.29  6.38       7.96 7.03%.                                     ______________________________________                                    

EXAMPLE 21 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed by using 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiouroniumbromide and 1-chloro-3-(4-methyl-1-piperazinyl)-2-propanol as startingmaterials to give the named product in a yield of 1.7 g, m.p.: 243° C.(from 90% ethanol).

    ______________________________________                                        Analysis for C.sub.21 H.sub.32 Cl.sub.2 N.sub.4 O.sub.3 S (molecular          weight 491.48)                                                                          C    H          N      S                                            ______________________________________                                        calculated: 51.32  6.56       11.40                                                                              6.52%;                                     found:      51.35  6.61       11.24                                                                              6.57%.                                     ______________________________________                                    

EXAMPLE 22 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-methyl-piperazinyl)propyl]mercaptoacetonitrilehydrochloride

The process described in Example 1 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1-chloro-3-(4-methyl-1-piperazinyl)-2-propanol as startingsubstances to yield 1.8 g of the named hydrochloride, which crystallizeswith 2.5 moles of crystal water from 96% ethanol, m.p.: 220° C.

    ______________________________________                                        Analysis for C.sub.23 H.sub.36 Cl.sub.2 N.sub.4 O.sub.3 S.2.5H.sub.2 O        (molecular weight 564.57)                                                               C    H          N      S                                            ______________________________________                                        calculated: 48.93  7.32       9.92 5.68%;                                     found:      48.96  7.05       10.15                                                                              6.05%.                                     ______________________________________                                    

EXAMPLE 23 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-acetoxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride

After adding 80 ml of benzene and 32 ml of acetic acid anhydride to 4.8g of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile,the reaction mixture is refluxed for 2 hours, then evaporated to drynessunder reduced pressure. The residue is dissolved in isopropanol andacidified by adding abs. ethanolic hydrogen chloride solution to givethe title hydrochloride in a yield of 4.72 g, m.p.: 204° C. (from abs.ethanol).

    ______________________________________                                        Analysis for C.sub.22 H.sub.30 ClN.sub.3 O.sub.5 S (molecular weight          484.01)                                                                                C    H        N      Cl     S                                        ______________________________________                                        calculated:                                                                              54.59  6.25     8.68 7.33   6.63%;                                 found:     54.37  6.16     8.90 7.41   6.39%.                                 ______________________________________                                    

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3         4.5    hours                                   Percentage of the                                                                         -33.8    -30.9     -29.5                                          protective effect                                                             ______________________________________                                    

EXAMPLE 24 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-acetoxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile

After adding 50 ml of benzene and 20 ml of acetic acid anhydride to 3.0g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile,the reaction mixture is refluxed for 1 hour, then evaporated to drynessunder reduced pressure. After addition of ether, the residuecrystallizes out to give the named product in a yield of 2.47 g, m.p.:133° C. (from isopropanol).

Analysis for C₂₄ H₃₃ N₃ O₅ (molecular weight 475.59): calculated: N8.84; S 6.74%; found: N 8.71; S 6.66%.

Inhibition of the constrictive action of acetylcholine: pd'₂ : 5.02.

Inhibition of the constrictive action of serotonin: pd'₂ : 5.05.

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3         4.5    hours                                   Percentage of the                                                                         -25.8    -20.3     -20.0                                          protective effect                                                             ______________________________________                                    

EXAMPLE 25 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-benzoyloxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile

After adding 40 ml of benzene, 1.0 g of triethylamine and 1.5 g ofbenzoyl chloride to 4.06 g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile,the reaction mixture is refluxed for 45 minutes, then cooled down andfiltered. After evaporating the filtrate, the residue crystallizes outon adding ethyl acetate to obtain the named product in a yield of 3.25g, m.p.: 144° C. (from isopropanol).

    ______________________________________                                        Analysis for C.sub.27 H.sub.31 N.sub.3 O.sub.5 S (molecular weight            509.61)                                                                                 C    H          N      S                                            ______________________________________                                        calculated: 63.63  6.13       8.25 6.29%;                                     found:      64.03  6.37       8.58 6.37%.                                     ______________________________________                                    

Inhibition of the constrictive action of acetylcholine: pd'₂ : 4.81.

Results of the carrageenin-induced rat paw edema test

    ______________________________________                                        50 mg/kg (p.o.)                                                                           1.5      3         4.5    hours                                   Percentage of the                                                                         -26.6    -17.7     -16.0                                          protective effect                                                             ______________________________________                                    

EXAMPLE 26 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-benzoyloxy-3-(4-morpholinyl)-propyl]mercaptoacetonitrilehydrochloride

40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chlorideare added to 4.34 g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrileand the reaction mixture is refluxed for 45 minutes, then cooled down.After filtering and evaporating the solvent under reduced pressure, theresidue is dissolved in isopropanol and acidified by adding abs.ethanolic hydrogen chloride solution. In this way 3.77 g of the namedhydrochloride crystallize out, m.p.: 207° C. (from ethanol).

    ______________________________________                                        Analysis for C.sub.29 H.sub.36 ClN.sub.3 O.sub.5 S (molecular weight          574.13)                                                                               C      H      N         Cl   S                                        ______________________________________                                        calculated:                                                                             60.66    6.32   7.32    6.18 5.59%;                                 found:    60.80    6.37   7.22    6.24 5.88%.                                 ______________________________________                                    

Inhibition of the constrictive action of acetylcholine: pd'₂ : 4.81.

EXAMPLE 27 Preparation of(-)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitriled-camphorsulfonate

The mixture containing 8.0 g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoaceetonitrileand 3.9 g of d-camphorsulfonic acid in 50 ml of abs. ethanol is heateduntil dissolution of the solid material (a few minutes). After coolingdown the crystalline precipitate is filtered and recrystallized from 40ml of hot abs. ethanol to give 5.0 g of the named salt, m.p.: 172° C.

The base is liberated by adding sodium hydroxide to an aqueous solutionof the camphorsulfonate salt. The base melts at 97° C., [α]=-11.3° (c=1,chloroform).

The hydrochloride of the product can be precipitated from anhydrousethanolic solution by adding anhydrous ethanolic hydrogen chloridesolution.

EXAMPLE 28

a) Preparation of(+)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride

The ethanolic mother liquor of the salt separation described in Example27 is evaporated to dryness under reduced pressure and water is added tothe residue. After alkalizing the solution obtained by 10% sodiumhydroxide solution, the separated oily yellow material is extracted intochloroform. After drying the chloroform solution over anhydrous sodiumsulfate and evaporating the solvent under reduced pressure, the residueis dissolved in abs. ethanol and acidified by adding ethanolic hydrogenchloride solution. The named hydrochloride is obtained in a yield of2.65 g, m.p.: 201° C. (from abs. ethanol), [α]=7.7° (c=1, water).

b) Preparation of(+)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile1-camphorsulfonate

The process described in Example 27 is followed by using 8.0 g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrileand 3.9 g of 1-camphorsulfonic acid as starting substances to obtain 5.2g of the named camphor-sulfonate salt, m.p.: 169°-170° C. (from abs.ethanol).

EXAMPLE 29 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride

After adding 4 ml of 10% sodium hydroxide solution and 6 ml of ethanolto 0.48 g of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-acetoxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride (product of Example 23), the reaction mixture is refluxedfor 30 minutes, then ethanol is evaporated under reduced pressure. Theoily residue crystallizes out, it is filtered, washed with water anddried. The product obtained is dissolved in 5 ml of abs. ethanol underheating and the solution is acidified by abs. ethanolic hydrogenchloride solution to give 0.4 g of the named hydrochloride which isidentical to the product of Example 17, m.p.: 210° C.

EXAMPLE 30 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrilehydrochloride

After adding 4 ml of 10% sodium hydroxide solution and 6 ml of ethanolto 0.48 g of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-acetoxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile(product of Example 24), the reaction mixture is refluxed for 30minutes. After evaporation of the solvent, the residue is extracted withchloroform. The organic solution is dried over anhydrous sodium sulfate.After evaporating the solvent, the residue is dissolved in 5 ml ofanhydrous ethanol under heating and acidified by abs. ethanolic hydrogenchloride solution to obtain 0.38 g of the named hydrochloride, which isidentical to the product of Example 18, m.p.: 203° C.

EXAMPLE 31 Preparation of2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-piperidinyl)propyl]mercaptoacetonitrilehydrochloride

After dissolving 3.85 g ofS-[α-cyano-α-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide in the mixture of 80 ml of methanol and 20 ml of water, 11.0 mlof 10% sodium hydroxide solution are added, the reaction mixture isrefluxed for 2 hours and a solution containing 1.44 g of1,2-epoxy-3-(1-piperidinyl)propane [prepared as described in J. Am.Chem. Soc. 80, 1257 (1958)] dissolved in 5 ml of methanol is addeddropwise to the hot solution. The reaction mixture is refluxed foradditional 5 hours. After evaporating methanol under reduced pressurethe reaction mixture is worked up as described in Example 1 to obtain2.3 g of the named hydrochloride which is identical to the product ofExample 15, m.p.: 210° C. (from anhydrous ethanol).

EXAMPLE 32 Preparation of2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(1-piperidinyl)propyl]mercaptoacetonitrilehydrochloride

The process described in Example 31 is followed by using 4.15 g ofS-[α-cyano-α-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl]isothiuroniumbromide and 1.41 g of 1,2-epoxy-3-(1-piperidinyl)propane to give 2.6 gof the named hydrochloride, m.p.: 192° C.

We claim:
 1. A process for the preparation of a racemic or opticallyactive compound of the formula (I) ##STR12## wherein R means hydrogen ora straight or branched chain C₁₋₆ alkoxy group;R¹ stands for hydrogen ora straight or branched chain C₁₋₆ alkyl group; R² represents hydrogen ora straight or branched chain C₁₋₆ alkyl group; R³ means hydrogen; astraight or branched chain C₁₋₆ alkyl group optionally substituted byone or two hydroxyl and/or one or two straight or branched chain C₁₋₄alkoxy group(s); or a C₄₋₇ cycloalkyl group; R⁴ stands for hydrogen or astraight or branched chain C₁₋₆ alkyl group optionally substituted byone or two hydroxyl and/or one or two straight or branched chain C₁₋₄alkoxy group(s); or a C₄₋₇ cycloalkyl group; and R³ and R⁴ together withthe nitrogen atom, to which they are attached form a 4 to 8-memberedcyclic group of formula ##STR13## optionally substituted by one or twostraight or branched chain C₁₋₄ alkoxy and/or one or two straight orbranched chain C₁₋₄ alkyl group(s), where optionally an oxygen or sulfuratom or an N-R⁵ group may be substituted for a ring carbon atom, whereR⁵ means hydrogen or a straight or branched chain C₁₋₆ aliphatic alkylgroup, the 4- to 8-membered cycle optionally being condensed with abenzene ring; R⁶ stands for hydrogen or a C₁₋₁₀ acyl group and the saltsthereof as well as hydrates of the free compounds of formula (I) and thesalts thereof, which comprises hydrolyzing a compound of the formula(II), ##STR14## wherein X is a halide ion, then reacting the obtainedsalt of the formula (III) ##STR15## wherein Me is a metal atom a) with aracemic or optically active compound of the formula (IV), ##STR16##wherein Y is halogen or arylsulfonyl, or with a compound of the formula(V) ##STR17## then, if desired, acylating the thus obtained activecompounds of the formula (I), wherein R⁶ stands for hydrogen, to obtaincompounds of the formula (I), wherein R⁶ is as defined above, excepthydrogen; or resolving the racemic compounds of formula (I); orconverting the racemic or optionally active compounds of formula (I) totheir salts; or liberating the free compounds of formula (I) from theirsalts; or liberating the free racemic or optically active compounds offormula (I) from their salts.
 2. A process as claimed in claim 1, whichcomprises reacting the compounds of formula (III) without isolating themwith the compounds of formula (IV) or (V), respectively.